Comparative anti‐inflammatory activities of antagonists to C3a and C5a receptors in a rat model of intestinal ischaemia/reperfusion injury

Abstract

1 Complement activation is implicated in the pathogenesis of intestinal ischaemia-reperfusion injury (I/R), although the relative importance of individual complement components is unclear. A C3a receptor antagonist N(2)-[(2,2-diphenylethoxy)acetyl]-L-arginine (C3aRA) has been compared with a C5a receptor antagonist (C5aRA), AcF-[OPdChaWR], in a rat model of intestinal I/R. 2 C3aRA (IC 50 ¼ 0.15 mM) and C5aRA (IC 50 ¼ 0.32 mM) bound selectively to human polymorphonuclear leukocyte (PMN) C3a and C5a receptors, respectively. Effects on circulating neutrophils and blood pressure in the rat were also assessed. 3 Anaesthetised rats, subjected to intestinal ischaemia (30 min) and reperfusion (120 min), were administered intravenously with either (A) the C3aRA (0.1-1.0 mg kg À1 ); the C5aRA (1.0 mg kg À1 ); the C3aRA þ C5aRA (each 1.0 mg kg À1 ); or vehicle, 45 min prior, or (B) the C3aRA (1.0 mg kg À1 ) or vehicle, 120 min prior to reperfusion. 4 The C3aRA and C5aRA, administered 45 min prior to reperfusion, displayed similar efficacies at ameliorating several disease markers (increased oedema, elevated ALT levels and mucosal damage) of rat intestinal I/R. The combination drug treatment did not result in greater injury reduction than either antagonist alone. However, doses of the C3aRA (0.01-10 mg kg À1 ) caused transient neutropaenia, and the highest dose (10 mg kg À1 ) also caused a rapid and transient hypertension. 5 The C3aRA (1.0 mg kg À1 ), delivered 120 min prior to reperfusion to remove the global effect of C3aRA-induced neutrophil sequestration, did not attenuate the markers of intestinal I/R, despite persistent C3aR antagonism at this time. 6 C3aR antagonism does not appear to be responsible for the anti-inflammatory actions of this C3aRA in intestinal I/R in the rat. Instead, C3aRA-mediated global neutrophil tissue sequestration during ischaemia and early reperfusion may account for the protective effects observed.

Complement Receptors in Inflammation

“…Systemic inhibition of C3a with a C3aR antagonist minimally resolves myocardial I/R injury, and neutropenia rather than C3aR antagonism appears to be responsible for C3aR antagonistassociated improvement in myocardial I/R injury (Busche and Stahl, 2010). These results confirm similar observations from previous studies (Ames et al, 2001, Proctor et al, 2004, indicating that C3aR antagonist-mediated neutrophil tissue sequestration during I/R injury may account for the protective effects observed. Overall, the data indicate while C3a/C3aR inhibition in the clinical setting of I/R injury does not appear to be therapeutic, targeting C5a as well as C5aR may be a promising approach to prevent I/R injury.…”

The receptor for complement component C3a mediates protection from intestinal ischemia-reperfusion injuries by inhibiting neutrophil mobilization

“…Whereas C5a has clearly been shown to recruit tissue neutrophils and to be a pathogenic factor in numerous IR injury models (3), the role of the upstream anaphylatoxin C3a has been relatively unexamined in IR injuries, owing in part to a lack of selective C3aR inhibitors (8,26,27). Given this situation, and considering the paucity of data on the role of C3a in IR injuries and neutrophil function, we used genetic elimination of C3aR to evaluate its impact on the development of intestinal IR injury in a neutrophil-dependent injury model.…”

C3a Receptor Modulation of Granulocyte Infiltration after Murine Focal Cerebral Ischemia is Reperfusion Dependent

“…They were housed in certified barrier facilities in microisolator cages with free access to food and water on a 12-h-light/12-h-dark cycle. C3a receptor antagonist (SB290157) purchased from Calbiochem (Darmstadt, Germany), or an equal volume of vehicle (10% ethanol in water), was administered via intraperitoneal injection (1 mg/kg) in a masked fashion 45 mins before, or 1 h after, ischemic onset; we used a dosing strategy similar to those used in earlier studies (Ames et al, 2001;Mocco et al, 2006;Proctor et al, 2004).…”